Cardiac Dysfunction in the Met Syndrome: Cross-talk between IR and bAR Signaling

Met 综合征中的心脏功能障碍：IR 和 bAR 信号传导之间的串扰

• 批准号: 9272923
• 负责人: E Dale Abel
• 金额: $ 38.69万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272923
• 关键词: ADRBK1 gene; Acute; Address; Adenylate Cyclase; Adrenergic Agents; Affect; Animals; Apoptosis; Attenuated; Biosensor; California; Cardiac; Cardiac Myocytes; Cardiomyopathies; Chronic; Collaborations; Complex; Coupling; Cross Syndrome; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Diet; Fatty acid glycerol esters; Functional disorder; Gene Targeting; Generations; Genetic; Genetic Transcription; Glucose Intolerance; Goals; Heart; Heart failure; Human; Hyperinsulinism; Hyperlipidemia; Hypertrophy; IRS1 gene; Impairment; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Iowa; Isoproterenol; Knock-out; Laboratories; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Remodeling; Link; Liver; Mediating; Metabolic; Metabolic Diseases; Molecular; Mus; Muscle Cells; Myocardial; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Phosphorylation; Physiological; Population; Prevention; Production; Proteins; Risk Factors; Role; Series; Signal Pathway; Signal Transduction; Skeletal Muscle; Testing; United States; Universities; Ventricular; Ventricular Remodeling; Yang; base; constriction; desensitization; epidemiology study; glucose uptake; in vivo; insulin sensitivity; insulin signaling; mortality; mouse model; mutant mouse model; novel; phosphodiesterase IV; phospholamban; pressure; prevent; protein degradation; public health relevance; response; trafficking; type I diabetic; western diet

DESCRIPTION (provided by applicant): Obesity, type 2 diabetes (T2DM) and insulin resistance are independent risk factors for heart failure, which affects a rapidly increasing segment of the US population. The long-term goal of this proposal is to understand the mechanisms linking these metabolic disorders and left ventricular (LV) dysfunction prior to and in concert with heart failure. Obesity is associated with insulin resistance, hyperlipidemia, glucose intolerance and hyperinsulinemia. Epidemiological studies suggest that hyperinsulinemia is an independent risk factor for heart failure. In humans and mouse models, the heart may retain its insulin sensitivity in terms of insulin's ability to activate IRS1, PI3K ad Akt signaling, despite insulin resistance in other organs such as the liver and skeletal muscle. This hyperinsulinemia also accelerates adverse LV remodeling in pressure overload hypertrophy and genetic reduction of insulin signaling in cardiomyocytes limits hypertrophic remodeling and reduces apoptosis in pressure overload, thereby preserving LV function. Our recent studies reveal that hyperinsulinemia desensitizes �R-mediated stimulation of cardiac contractility, which represents a novel mechanism linking insulin resistance, hyperinsulinemia and LV dysfunction. This proposal, will therefore focus on the hypothesis that hyperinsulinemia might attenuate LV contractility by directly impairing �or �-adrenergic (�) signaling. Specifically, activation of cardiomyocyte insulin receptors (IR) in hyperinsulinemic states, impairs � signaling via two distinct mechanisms: (1) Increased �R/Gi coupling that inhibits adenylyl cyclase and cAMP production, and (2) Increased expression of PDE4D that increases cAMP degradation. This multi PI proposal reflects an active collaboration by the laboratories of Evan Dale Abel (University of Iowa) and Yang Kevin Xiang (University of California -Davis). Our combined expertise in myocardial insulin signaling and myocardial adrenergic signaling will address this hypothesis in the following two specific aims. Aim 1 (Xiang). Will define the molecular mechanisms by which insulin impairs � signaling in cardiomyocytes by testing the following hypotheses: Insulin signaling increases �R/Gi coupling via a complex containing �R, IR, IRS, and GRK2 that inhibits adenylyl cyclase-mediated cAMP generation. Insulin signaling enhances cardiac PDE4 levels via �R-ERK dependent modulation of PDE4 transcription and protein turnover. Aim 2 (Abel). Will determine the physiological consequences of �-IR interactions in hearts in vivo by testing the hypotheses that: Acute or chronic hyperinsulinemia will impair myocardial � signaling and reduce contractility or inotropic reserve and that hyperinsulinemia in obesity, T2DM and heart failure will exacerbate cardiac dysfunction by impairing inotropic reserve. By using novel molecular biosensors to define subcellular adrenergic signaling domains in cardiomyocytes and a comprehensive array of mutant mouse models with perturbed IR or � signaling, we will dissect the mechanism for IR-� crosstalk that limits myocardial contractility in insulin resistant states.

描述（由申请人提供）：肥胖、2型糖尿病（T2 DM）和胰岛素抵抗是心力衰竭的独立风险因素，影响了美国人口的快速增长部分。本提案的长期目标是了解这些代谢紊乱与心力衰竭前和心力衰竭时左心室（LV）功能障碍之间的联系机制。肥胖与胰岛素抵抗、高脂血症、葡萄糖耐受不良和高胰岛素血症有关。流行病学研究表明，高胰岛素血症是心力衰竭的独立危险因素。在人类和小鼠模型中，尽管其他器官（如肝脏和骨骼肌）存在胰岛素抵抗，但心脏可能在胰岛素激活IRS 1、PI 3 K和Akt信号传导的能力方面保持其胰岛素敏感性。这种高胰岛素血症还加速了压力超负荷肥大中的不利LV重构，并且心肌细胞中胰岛素信号传导的遗传减少限制了肥大重构并减少了压力超负荷中的细胞凋亡，从而保护了LV功能。我们最近的研究表明，高胰岛素血症脱敏R介导的心脏收缩力的刺激，这代表了一种新的机制连接胰岛素抵抗，高胰岛素血症和左室功能障碍。因此，这项建议将集中在高胰岛素血症可能通过直接损害β或β-肾上腺素能（β）信号而减弱LV收缩力的假设上。具体来说，高胰岛素血症状态下心肌细胞胰岛素受体（IR）的激活通过两种不同的机制损害β信号传导：（1）增加β R/Gi偶联，抑制腺苷酸环化酶和cAMP的产生，（2）增加PDE 4D的表达，增加cAMP降解。该多PI提案反映了Evan Dale Abel（爱荷华州大学）和Yang Kevin Xiang（加州-戴维斯大学）实验室的积极合作。我们在心肌胰岛素信号传导和心肌肾上腺素能信号传导方面的综合专业知识将在以下两个具体目标中解决这一假设。目标1（Xiang）。将通过测试以下假设来定义胰岛素损害心肌细胞中信号传导的分子机制：胰岛素信号传导通过含有R，IR，IRS和GRK 2的复合物增加R/Gi偶联，该复合物抑制腺苷酸环化酶介导的cAMP生成。胰岛素信号通过R-ERK依赖性调节PDE 4转录和蛋白质周转来增强心脏PDE 4水平。目标2（阿贝尔）。将通过测试以下假设来确定体内心脏中β-IR相互作用的生理后果：急性或慢性高胰岛素血症将损害心肌信号传导并降低收缩力或正性肌力储备，肥胖、2型糖尿病和心力衰竭中的高胰岛素血症将通过损害正性肌力储备而加剧心功能障碍。通过使用新型分子生物传感器来定义心肌细胞中的亚细胞肾上腺素能信号结构域以及一系列IR或β信号受到干扰的突变小鼠模型，我们将剖析IR-β串扰限制胰岛素抵抗状态下心肌收缩力的机制。